Dengue is the most common mosquito-borne viral disease in the world with no approved therapeutic treatment or vaccine to help those exposed to the virus. World Health Organization estimates that 40% of the world's population is at risk from Dengue with approximately 100 million cases annually. For the most part, Dengue is self-limiting albeit with debilitating symptoms including fever, rash, pain behind the eyes, joint and muscle pain. However, severe forms of Dengue including Hemorrhagic Fever and Dengue Shock Syndrome can occur in approximately 500,000 people leading to hospitalization each year, many of whom are children. About 2.5-5% of severe Dengue patients die each year. There are four distinct serotypes of dengue viruses that have made vaccine development a challenge. There is little to no cross immunity among the serotypes and immunity to one serotype puts an individual at risk of developing an immuno-pathological response when infected by another serotype. An alternative to vaccine development is a broad-spectrum dengue antiviral drug. Here we provide an innovative approach to identify novel inhibitors of the assembly of the dengue RNA replication complex. In this case, we have designed a cell-based assay to find small-molecule compounds that block NS3 helicase binding with NS5 RNA dependent RNA polymerase. These subunits associate at highly conserved interaction sites found across all four serotypes. Further, mutagenesis studies show that the interaction of both proteins is essential for viral production. An initial screen of 10,000 diverse compounds has identified one compound that selectively disrupts NS3-NS5 interaction in the HTS assay while an additional 50,000 compounds remain to be screened. Using this approach followed by validation of select candidate compounds in a dengue viral replication assay, we propose to identify inhibitory compounds acting at a novel Dengue target site for the development of a much-needed broad-spectrum Dengue drug therapy.